Timmis synthesis

Acid-catalysed condensation of 1,3-indanedione with a nitrosoaminopyrimidine gives a new pyrazine ring—a type of cyclization sometimes known as the Timmis synthesis. Another indanedione derivative, 2,2-dihydroxy-1,3-Indanedione, condenses with a nitrosoamine with even better results and without the need for acid to be present. 

The second major method for the synthesis of pteridines involves the condensation of a 5-nitrosopyrimidin-4-amine with an a-oxomethylene compound. The formation of 7-methyl-6-phenylpteridine-2,4-diamine (1) from 5-nitrosopyrimidine-2,4,6-triamine and phenylacetone is generally known as the Timmis synthesis.120... 

The Timmis synthesis is a versatile reaction and a range of 2,6-substituted 5-nitrosopyrim-idin-4-amines can be condensed with a variety of a-oxomethylene compounds as well as a-methylenenitriles. Generally, the products have unambiguous structures as it is the nitroso group which condenses with the methylene group, and the amine with the carbonyl group. However, the yields which are obtained are often rather poor. 

An example of the use of the Timmis synthesis with an a-methylene ketone is the condensation of 5-nitroso-2-phenylpyrimidine-4,6-diamine with phenylacetone to give 7-methyl-2,6-diphenyl-pteridin-4-amine (1). The use of phenylacetaldehyde gives 2,6-diphenylpteridin-4-amine (2), but in less than 20% yield.121... 

Use of esters in the Timmis synthesis is exemplified by the formation of 4-amino-6-phenylpte-ridin-7(8i/)-one (1) from 5-nitrosopyrimidine-4,6-diamine and ethyl phenylacetate.122... 

Some further examples of the Timmis synthesis are given in Table 8. 

The Pachter modification of the Timmis synthesis is performed in the presence of cyanide ion,129 products other than those expected being obtained. For example, the condensation of phenylacetonitrile with 5-nitroso-2-phenylpyrimidine-4,6-diamine in the presence of cyanide ion gives, not 7-methyl-2,6-diphenylpteridin-4-amine but 2,6-diphenylpteridine-4,7-diamine (5).121 The mechanism of the reaction is still uncertain, but it may involve nucleophilic addition of cyanide ion to the Schiff base formed by condensation between the nitroso group and the active methylene, cyclization to yield a dihydropteridine, and subsequent elimination. 

Table 9. Examples of the Pachter Modification of the Timmis Synthesis...

Amino-5-nitrosopyrimidines 2 cyclocondense with systems possessing an activated CH2 group (aldehydes, ketones, nitriles, esters, reactive methylene compounds, phenacylpyridinium salts) providing pteridines 3 on base catalysis Timmis synthesis) ... 

The regioselectivity of the Timmis synthesis is demonstrated by condensation of the 4-amino-5-nitrosouracil (8), leading to l,3-dimethyl-6-phenyllumazine (7) with phenylac-etaldehyde or to the 7-phenyl isomer 9 with acetophenone ... 

Thorpe-Ziegler cyclization 431 Timmis synthesis (pteridine) 489 Traube synthesis (purine) 476... 

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